Section 1 Preformulation

Contents

1. Contents and Introduction

2. Tablet Processing

 Processing
 Scale-up

3. Tablet lngredients

 Wet Granulation
 Direct Compression

4 Tablet Problems and Remedies

 Problems and Remedies-Alphabetical

Index to 2 3, 4

5. Preformulation

6. Coating

7. Capsules

8. Suspensions

9. Emulsions

10. What is Avicel© Microcrystalline Cellulose?

11. Publications

 Avicel Bibliography

12. Avicel© MCC Literature

13. Technical Service

14. Avicel© MCC Availability Worldwide

15. Govemmental Approvals of Avicel©

Microcrystalline Cellulose

16. Compendia Listings of Avicel©

Microcrystalline Cellulose

17. Supplier Information

Introduction

This Problem Solver and Reference Manual covers a wide range of subjects of interest to the

pharmaceutical industry. It has been compiled from information generated by our Research and

Development, Technical Service. and Marketing departments, as well as from many outside

sources.

The first nine sections are devoted to pharmaceutical technology. These include sections on tablet

processing, ingredients, problems and remedies, preformulation, capsules, coatings, and liquids.

Sections 10-13 deal with Avicel© microcrystalline cellulose technology as it relates to pharmaceutical

products. The final sections cover information of a general nature that we believe will be of interest to

the formulator.

1984 FMC Corporation

Avicel-FMC Corporation trademark

EMG

Every effort has been made to be as complete and factual as possible. It is our intention to expand

and update this material as often as practical. We invite not only your comments, but also any new

information or corrections you deem appropriate.

Because many factors affect results, Avicel microcrystalline cellulose products are sold on the un-

derstanding that purchasers will make their own tests to determine the suitability of these products

for their particular applications. The several uses suggested by FMC Corporation are presented to

assist our customers in exploring possible applications for Avicel. All information and data presented

are believed to be accurate and reliable, but are presented without responsibility on the part of

FMC Corporation.
Preformulation
FIMG

Section 5

Contents
Introduction

Physical Description

Microscope Examination

Particle Size

Partition Co-efficient and Dissociation

Constant (pKa)

Polymorphism

Solubility

Dissolution

Stability

Excipients

Membrane Permeability

Summary

Bibliography
Introduction

Preformulation, in the broadest sense, encompasses all the activities and studies required
to prepare

an active pharmacological substance into a form suitable for administration to humans.

Although preformulation testing has been “formalized” in many firms in the recent past, the
activities of the

preformulation group, out of necessity, have always been carried out. The extent and
sophistication of modern preformulation studies are a reflection of advances made in all
aspects of pharmaceutical sciences. Significant impact has resulted from improved
techniques for qualitative and quantitative measurements as well as increased demand due
to regulatory requirements.

The object of formulation activities is to prepare a drug delivery system or dosage form to
produce an optimum effect. However, the active substance must always be stable for &
reasonable period of time in the formulated state and capable of being produced on highly
efficient manufacturing equipment. Therefore, pharmaceutical product develop-

ment consists of formulating an active pharmacological agent to a convenient dosage

system which is manufacturable, stable, and bioavailable.

In the early stages Of the pharmaceutical industry, ease of manufacture and palatability,
along with the characteristic known as "pharmaceutical ele-

gance,” were the prime considerations in dosage form development. The preformulation
studies at this time largely consisted of organoleptic tests such as taste and odor. The
results of such tests frequently necessitated sugar-coating the dosage forms. The concept of
stability became very important with the advent of mass-produced medicinas which would
be maintained on shelves and/or warehouses for long periods. The great effort which
centered around evaluation and prediction of stability is evidenced by the many articles
published in pharmaceutical literature during the middle of the 2oth Century. The criteria
for stability during this period generally became chemical stability, whereas previously,
physical stability was the major consideration, i.e., color changes, sedimentation, and
caking. This requirement for chemical stability highlighted the importance of
preformulation work. In addition, this need for stable products initiated many of the early
studies of kinetics and reaction mechanisms of important pharmacological agents. This
basic information was necessary in order to stabilize the product and/or prevent
incompatibilities with pharmaceutical excipients.

The next important criteria to have a major impacton dosage form development was the
concept of bioavailability. The importance of bioavailability was recognized in the 1950's
and was continually extended during the decade of the 1960's. This concept. spurred by
development of sophisticated analytical instrumentation which permitted blood level
studies of. low dose potent drugs, demanded a formalization of a preformulation program.
This was a necessity to avoid costly development programs on inadequate or inappropriate
forms of the active substance and/or drug delivery system.

Flarer is a drug of itself used in therapy. Drugs must be administered in pharmaceutical

dosage forms, and it is these drug products that are pre-scribed and dispensed to a patient.
Drug products should have adequate stability, uniform composition, preservation
protection, and proper packaging. Timer and thorough preformulation research allows for
easier and more efficient formulation development.

Preformulation work, in most cases, begins after a compound is identified as a candidate for
human clinical testing. At this point, requests for dosage forms are submitted to the
Pharmacy Research and Develºpment Department. The depth of the initial studies will
depend, to a large extent. on the availability of the initial drug supply and the intended
route of administration. Some of the most important properties which must be highlighted
are particle size, solubility, partition co-efficient, dissolution characteristics. crystal form and
size, and stability. The importance of these parameters candepend to a great extent on the
intended use of the drug. For instance, if no liquid dosage forms are contemplated, solution
stability is far less important than in most cases where parenteral or oral solution
administration is the desired route.
As stated earlier, preformulation studies have always been necessary. However, the
development of a formal or planned preformulation program is relatively new. Whether
this is accomplished by a group in the pharmaceutical companies specifically charged with
preformulation or whether the information is gathered in various areas of the company and
collated by the formulation department is inconsequential. There are advantages and
disadvantages to both systems. However, the important fact is that the required
information is obtained and transmitted to the formulator prior to extensive formulation
work in order to avoid serious delays and/or major changes in formulation during extensive
clinical studies.

At the time preformulation studies are initiated, the medicinal chemist has already
evaluated the compound as to structure and purity and selected physical-chemical
characteristics, such as melting point. This information, in conjunction with the intended
use, is the basis for the preformulation plan.

The following is a description of the types of studies which should be considered in a

preformulation program. The information obtained and some of the more important
experimental techniques employed are also discussed.

Physical Description

It is important to have a formal physical description of the early batches of drug substance
for comparison with later submissions. This includes color, odor, and taste. All of these
organoleptic properties can be important in dosage form development considerations,
depending on the intended route of administration and dosage forms. For instance, a

foul tasting substance intended for use in a pediatric suspension or solution form may
require development of a less soluble salt or utilization of coating techniques.
Microscope Examination

Microscope examination, including SEM photo micrographs of the raw material, is an

important facet of preformulation testing. This gives an indication of particle size and range
of the raw material as well as crystal habit. Photomicrographs of the initial and subsequent
lots can provide important information should difficulty arise in processing due to some
change in the crystal or particle characteristics of the drug on scale-up and/or changes in
synthesis.

Particle Size

A number of physical and chemical properties of drug substances are affected by the
particle size distribution. Drug dissolution rate, bioavailability, content uniformity, taste,
texture, color, and stabilty are all dependent to varying degrees on particle size distribution
of pharmacological agents. In addition, properties such as flow characteristics and

sedimentation rates, among others, are also important factors related to particle size. It is
essential to establish at an early time if a relationship exists between the particle size of the
active ingre-dient and the important formulation characteristics.

Of special interest is the highly important and well documented effects of particle size on
absorption of certain drugs. For example, particle size has been shown to significantly
influence the oral absorption profiles of griseofulvin, nitrofurantion, spiranolactone, and
procaine penicillin. Satisfactory content uniformity in solid dosage forms depends to a large
degree on particle size and distribution of the active ingredient, particularly for drugs with
high potency with resulting low active to excipient ratios. It is obvious that the particle size
and distribution of active agents must be optimized, monitored, and controlled where
applicable. It is crucial that the particle size requirements be established in the early
preformulation stage to insure development of formulations with acceptable bioavailability,
stability, and ease of manufacture.

There are many methods available to evaluate particle size and distribution; however, only
those used extensiver in the pharmaceutical industry will be considered here. These are
sieving or screening, microscopy, sedimentation, and stream scanning.
For powders in the range of approximately 44 microns and greater, sieving or screening is
the most widely used method of size analysis. The difficulty with using this method early in
the preformulation program is the requirement of a relatively large sample size. There are
other disadvantages to this technique, such as blinding due to clogging of a screen. Use of
an Air Jet sieve or Sonic Sifter may overcome these disadvantages. The main advantage of
the sieve method is simplicity, both in technique and equipment requirements.

Optical microscopy is frequently the first determination of particle size and shape on a new
product. This is usually a qualitative assessment since quantitation by the microscope
technique is tedious and time consuming. A key element in utilizing the microscope for
particle size determination is preparation of the slide. It must be representative of the bulk
of the material and be properly suspended and thoroughly dispersed in a suitable liquid
phase. In order to do a quantitative particle

FEMJG

size evaluation, the particles counted should be in the range of 1,000.

Sedimentation techniques utilize the relationship between rate of fall of particles and their
size. A number of classical techniques, based on sedimentation methods, utilizing devices
such as the Andreasen pipet or recording balances that continuously collect a settling
suspension, are available.

These methods share the disadvantage of the microscope technique in that it is tedious to
obtain the data and precautions in experimental techniques must be observed. Proper
dispersion, consistent sampling, temperature control, and other experimental variables
must be carefully controlled in order to obtain consistent and reliable results.
Stream scanning is another valuable method for determining particle size distribution of
powdered drug substances. This technique utilizes a fluid suspension of particles which pass
the sensing zone where individual particles are sized, counted, and tabulated. Sensing units
may be based on light soattering or transmission as well as conductance. Two popular units
in the pharmaceutical industry for this purpose are the Colter Counter and Hiac Counter.
Both units electronically size, count, and tabulate the individual particles that pass through
the sensing zone. This technique has obvious advantages in that data can be generated in a
relatively short time with reasonable accuracy.

Thousands of particles can be counted in seconds and used to determine the size
distribution curve…

All stream scanning units convert the particles to effective diameter, and therefore have the
shortcoming of not providing information relative to particle shape. Nevertheless, stream
scanning methods are powerful tools and can be used for evaluation of such parameters as
crystal growth in suspension formulations.

Partition Co-efficient and Dissolution Constant (pKa)

In order to produce a biological response, the drug molecule must first cross a biological
membrane.

The biological membrane acts as a lipid barrier tomost drugs and permite the absorption of
lipid soluble substances by passive diffusion while lipid insoluble substances can diffuse
across the barrier only with considerable difficulty, if at all. The interrelationship of the
dissociation constant, lipid solubility, and pH at the absorption_site and absorption
characteristics of various drugs are the bases of the pH-partition theory.

The oil/war partition co-efficient is a measure of the molecule's lipophilic character. A

measurement of this characteristic, particularly if a series of homologous agents are being
considered, can be very important in estimating the potential efficiency of the agent as a
drug candidate. Methods of determining the partition co-efficient are relatively
straightfowvard. The drug is added to & mixture of a pair of immiscible solvents. For
example, octanol/water is a popular combination, and concentration at equilibrium in each
of the solvents is measured and the partition co-efficient calculated.

Specifically, the amount of drug in the lipid portion is divided by the amount of drug in the
aqueous portion.

Partition co-efficients can also be estimated by various chromatographic procedures, for

example, thin layer chromatography.

A large number of drugs are either weakly acidicor weakly basic compounds. Accordingly,
depending on the pH value, the compound exists in solution phase as ionized or un-ionized
species. The un-ionized species are more lipid soluble and hence more likely to elicit the
pharmacological response. The determination of the degree of ionization or pKa value of
the drug substance is an irnportant physical-chemical characteristic relative to evaluation of
possible effects on absorption from various sites of administration.

Dissociation constant or pKa is usually determined by potentiometric titration.

Polymorphism

Another important factor having a bearing on the pharmaceutical and biopharmaceutical

properties of a drug substance is the crystal form of the agent. The ability of a substance to
exist in more than one crystal form is a property known as poly-morphism. Polymorphic
forms usually exhibit different physicaI-chemical properties, including melting point and
solubility. At any temperature and pres-sure, only one polymorphic crystal form of a
compound will be stable. Under the same conditions, another polymorphic form will
convert to the stable form. If this conversion to the more stable form is relatively slow, a
specific polymorph may have advantages as far as pharmaceutical properties are
concerned. Such a slowly converting form is known as a metastable form and can, in many
cases, be considered stable for pharmaceutical purposes.

The occurrence of polymorphic forms with drugs is relatively common, and it has been
estimated that polymorphism is exhibited by at least one-third of all organic compounds.
For certain classes of drugs, the instances of polymorphism are even greater. For example,
approximately one-half of the 22 barbituric acid derivatives and 11 of the 16 steroids that
were investigated displayed polymorphism. At least five distinct crystal forms of cortisone
acetate have also been reported.

Aside from the polymorphic forms in which compounds may exist, they also can occur in
noncrystalline or amorphous forms. The energy required for a molecule of drug to escape
from a crystal is muCh greater than required to escape from an amorphous powder.
Therefore, the amorphous form of a compound is always more soluble than a
corresponding crystal form and may exhibit correspondineg different biopharmaceutical
and pharmaceutical properties. An example of such an

effect has been demonstrated for the various

forms of the antibiotic novobiocin.

it is obvious that many organic medicinal compounds which are capable of existing in more
than one crystal form are known. The resulting variation and physical-chemical properties
associated with differences in crystal form may be of considerable pharmaceutical
importance.

In addition to true polymorphic forms, many or-ganic medicinal compounds can form
solvent addition compounds. or solvates. When water is the solvent associated with the
drug moiety, the solvate form is called a hydrate. As with other crystal modifications, the
physical-chemical properties of a solvated form may differ significantly from that of a

nonsolvated form of the compound. For example,significant differences in the dissolution

rate of the anhydrous and hydrated forms of caffeine, the ophylline, and glutethamide have
been observed.

An interesting example of the differences in biologcal availability between an anhydrous

and hydrated form of a substance was noted for the amphoteric penicillin ampicillin.
It is clear from the foregoing that the evaluation of crystal structure, polymorphism, and
solvate form is an important preformulation activity. The changes in crystal characteristics
can influence methods are hot stage microscopy, thermal analysis, infrared spectroscopy,
and x-ray diffraction.

Solubility

An extremer important physical-chemical property

of drug substances is solubility, especially aque-

ous system solubility. The drug must possess

some limited aqueous solubility for therapeutic effi-

cacy. In order for a drug to enter the systemic cir-

culation to exert a therapeutic effect, it must first

be in solution. Relatively insoluble compounds

often exhibit incomplete or erratic absorption. If the

solubility of the drug substance is less than re-

quired for solubility of the recommended dose in

the gastrointestinal tract, consideration must be

given to improve its solubility. The methods to ac-

complish this will depend on the chemical nature

of the drug and the type of drug product under

consideration. For example, if the drug substance

is acidic or basic, solubility may be influenced by

changes in pH. The solubility of weakly acidic and

basic drug substances can be predicted as a func-

tion of pH by application of the law of mass action.

There are many drug substances for which pH ad-

justment is not effective as a means of improving

solubility. Very weak acidic or basic drugs may re-

quire extremes in pH that are outside accepted

physiological limits or may cause stability problems

with formulation ingredients. Adjustment of pH

normally has little effect on the solubility of non-

electrolyte substances. ln many cases, it may be

required to consider the utilization of co-solvents

Although poor solubility of the drug substance is

the most frequent concern, there are occasions

when a less soluble form is desired. A lower

aqueous solubility may be required to improve the

taste of 3 formula. An example of this is the use of

an insoluble form of clindamycin, clindamycin pa-

moate. Lower solubility may also be indicated in

those cases where it is desirable tó slow absorp»

tion to provide a prolonged action or in those in-

stances where the gastro-intestinal contents

degrade the active ingredient. In this latter circum=

stance, if the drug is relatively insoluble

in the inactivating system, a balance can be

Solubility data is also valuable to the formulator

relative to choosing the solvent for purposes of

granulation and coating.

Solubility is normally determined by the equilibrium

solubility method, wherein an excess of the agent

is placed in the solvent of interest and shaken at a

constant temperature over a prolonged period of

time until equilibrium is obtained.

Dissolution

Many variations of biological activity of a given

drug substance are brought about by the rate at which it becomes available to the
organism. ln

many instances, dissolution rate, or the time it

takes for the drug to dissolve in the fluids at the

absorption site, is the rate-Iimiting step in the ab-

sorption process. This is true for drugs adminis-

tered orally in solid forms such as tablets,

capsules or suspensions, as well as drugs admin-

istered intramuscularly in the form of pellets or

suspensions. When dissolution rate is the rate-lim-

iting step, anything which affects it will also affect

absorption. Consequently, dissolution rate

can affect the onset, intensity, and duration of re-

sponse, and control the overall bioavailability of

the drug from the dosage form.

The dissolution of a substance in a nonreacting

solvent may be described by the Noyes-Whitney

equation shown as equation 1.

KS (CS - C). (1)

The term dc/dt is the rate of solution, 8 is the sur-

face area of a dissolving solid, and K is the disso-

lution rate constant, which includes several factors,

such as intensity of agitation and the diffusion co-

efficient of a dissolved drug. The concentration of

the drug in the dissolution medium at some finite

time is represented by C, and CS is the concentra-

tion of the drug in the diffusion layer surrounding

the solid material. The diffusion layer is a thin film

saturated with drug. Accordingly, CS is essentially

equivalent to the concentration of a saturate solu-

tion of the drug in the solvent, and the rate of dif-

fusion of solute molecules through the diffusion

layer into the body of the solution. Examination of

the Noyes-Whitney equation suggests several

ways by which the dissolution rate of a drug may

be increased.

Since dissolution rate is directly proportional to

surface area, a decrease in particle size will result

in greater surface area and subsequently in more

rapid dissolution. Early observation of the effect of

particle size on blood levels was made with sev-

eral of the sulfa drugs, specifically, sulfadiazine

and sulfaethylthiadiazole. Griseofulvin is a drug

which provides one of the most striking examples

of the role dissolution rate and effect of surface

area play in biological availability. It was shown

that the amount of griseofulvin absorbed increased

linearly with an increase in the specific surface

area of this drug. These observations led to mar-

keting of micronized preparations of this drug

which permit a dosage reduction of 50% compared

to the original macro-forms.

Particle size reduction can be obtained in several

ways. Historically, this was accomplished by grind-

ing or micronization. More recently, particle size

reductions have been accomplished in a number

of instances by the preparation of microcrystalline

molecular dispersions of poorly soluble drugs in a

solid matrix of a water soluble carrier.

Although reducing particle size will influence disso-

lution rate in a positive direction, use of this tech-

nique to enhance absorption is limited to those

cases in which absorption is dissolution-rate lim-

ited. Normally, an increase in dissolution rate is of

little value for water soluble drugs or weekly basic

drugs administered as their salts since their ab-

sorption is usually not dissolution-rate limited. In

addition, there are instances in which particle size

reduction may result in an overall decrease in

bioavailability. For example, a situation may exist

in which a drug is unstable in.the gastric fluids;

rapid dissolution results in a more rapid degrada-

tion and an overall reduction in bioavailability.

The dissolution rate of drugs may also be in-

creased by increasing the solubility in the diffusion

layer. The most effective means of obtaining

higher dissolution rates is to use a highly water

soluble salt of the parent substance. Although a

soluble salt of a weak acid will subsequently pre-

cipitate as the free acid in the bulk phase of an

acidic solution, (such as gastric fluid) it will do so

in the form of very fine particles with a large sur-

face area. There are numerous reports in the liter-

ature to illustrate the influence of dissolution rate

of weak acids and their salts on the rate of drug

absorption, bioavailability, and therapeutic re-

sponse after oral administration.

High solubility is one of several factors affecting

the dissolution rate, but this property is not always necessarily associated with a high
dissolution rate.

lt must be understood that solubility refers to an

equilibrium condition, while dissolution is a kinetic'

process. Saturation is seldom reached in gastroin-

testinal fluids, and, since absorption and distribu=

tion processes constantly remove dissolved drug,

the important factor is how rapidly the solid drug

appears in solution in an absorbable and diffus-

able form. Important factors in dissolution rate

which must be considered by the prefórmulator are

particle size, surface properties of the drug, crystal

form, and chemical form. Although particle size re-

duction creates a greater surface area and will im-

prove dissolution rate, it should be kept in mind

that surface properties of the drug can result in

high surface energy of a micronized powder which

may retard dissolution. Usually, this is a result of

the powder demonstrating poor wettability and the

tendency to form agglomerates. As noted earlier,

metastable polymorphs have a greater dissolution

rate compared to the most stable form. Solvates

may also be considered in this category. The

chemical form of the substance, that is, free acid

or base or salt or ester form, can also result in sig-

nificant differences in dissolution rate.

Dissolution rates of chemical compounds can be

determined by two general methods: the constant

surface method which provides the intrinsic disso-

lution rate of the agent, and particulate dissolution

in which a suspension of the agent is added to a

fixed amount of solvent without exact control of

surface area.

The constant surface method utilizes a com-

pressed disc of known area. This method elimi-

nates surface area and surface electrical charges

as dissolution variables. The dissolution rate ob-

tained by this method is termed the intrinsic disso-

lution rate and is characteristic of each solid

compound and a given solvent under the fixed ex-

perimental conditions. The value is generally ex-

pressed as milligrams dissolved per minute centi-

meters squared (mg/min./cmº). lt has been

suggested that this value is useful in predicting

probable absorption problems due to dissolution

rate.
Particulate dissolution is obtained by adding a

weighed amount of powdered sample to the disse»

lution medium in a constant agitation system. Par»

ticulate dissolution is frequently used to study the

influence of particle size, surface area, and ex-

cipients upon the active agent. On occasion, an in-

verse relationship of particle size to dissolution is

noted due to the surface properties of the drug. In

these cases, surface charge and/or agglomeration

results in the reduced particle size form of the

drug presenting a lower effective surface area to

the solvent due to incomplete wetting or agglomer-

ation.

Studies on the effect of excipients on dissolution

of active compounds at an early stage can be of

great value to the formulator in developing the ini-

tial dosage forms and can be used as & bench-

mark in the evaluation of the early developed

forms.
Stability

One of the most important functions of a preformu»

lation group is the evaluation of the physical and

chemical stability of the pure drug substance. It is

essential that these initial studies be performed on

a drug of known purity. The presence of impurities

can lead to erroneous conclusions in such evalua-

tions. The types of stability studies initiated in the

preformulation phase are: 1) solid state stability of

the drug alone, 2) solution phase stability and 3)

compatibility studies, that is, stability in the pres-

ence of expected excipients.

These studies, ideally, should utilize a reliable sta-

bility indicating analytical method. However, at the

early preformulation stage, a stability indicating

method of analysis is frequently unavailable. Tech-

niques such as thin layer chromotography. thermal

analysis, and diffuse reflectance can be utilized to

provide data to assess preliminary stability.

Prime consideration must be given to stability of

the bulk chemical as early as possible. Initial in-

vestigation begins with examination of the chemi-

cal structure which allows the preformulation sci-

entist to anticipate the possible degradation reactions. For example, esters, lactams, and

amides are susceptible to solvolytic reaction while

the presence of unsaturation or electron rich cen-

ters predispose the molecule to free radical me-

diated or photo-catalyzed oxidation. With pre-

liminary deductions made from the chemical

knowledge, it is possible to design experiments to

identify the problem areas. It is not the prime ob-

jective in these early studies to establish the

mechanism ofdegradation; the more important

facets of the study are to identify the factors which

cause instability in drug substances of interest.

Generally, the effects of heat, light, oxygen, and

moisture are evaluated.

Drug substances may be stable, stable under spe-

cial handling conditions or unstable. The initial sta-

bility studies are designed to characterize which of

these classes the drug substance of interest falls.

In cases where the compound is found to have

stability problems, it then becomes important to

define the degradation mechanism and initiate

studies to stabilize the substance.

Hydrolysis, a solvolysis reaction, is probably the

most important degradation reaction of concern

with pharmaceutical products. Drugs are normally

exposed to water at some point in either process-

ing or storage, thereby presenting the conditions

for hydrolysis to occur. Hydrolysis can be influ-

enced by temperature and hydrogen or hydroxyl

ion concentration. The effects of temperature allow

for extrapolation of rates obtained at exaggerated

conditions to provide reasonable estimates of

shelf-life stability of potential new drug products. In

those cases where the hydrolysis reaction is sensi-

tive to hydrogen or hydroxyl ion concentration or is

pH dependent, studies can be designed to estab-

lish the pH of maximum stability. A pH stability

profile, a plot of the reaction rate against the pH of

the system, is one of the most powerful tools in

possession of the formulation pharmacist. This is

particularly true when liquid solution or suspension

dosage forms are being considered.

Oxidation is another process important in the deg-

radation of drug products. Oxidation reactions de-

pend on several factors including temperature,

oxygen concentration, and impurities which can

act as catalysts. Once it has been established that

the oxidation route is the principal mechanism for

degradation, the effect of additives can be eval-

uated as a means of stabilization. Other factors,

which also come into play during the study of the

oxidation process, are the effects of pH and light.

The presence of heavy metal ¡ons frequently cata-

Iyze such reactions and can be a particularly trou-

blesome problem when they are present in so

called inert or excipient ingredients.

The oxygen concentration in solution is a determi-

nant of the oxidative process, and since oxygen is

more soluble at lower temperatures, such reac-

tions often proceed more rapidly at the lower tem-

peratures. It is obvious that oxidation is a very

complex process and presents a formidable obsta-

cle to the formulation pharmacist. Experiments

must be designed to encompass many variables,

and conclusions' must be drawn, at best, on limited

and incomplete data.

Although solvolytic (hydrolytic) and oxidation reac-

tions are the most frequent types of degradation

encountered in drug substances, other mecha-

nisms also must be considered during the prefor-

mulation stage. For example, ºptically active sub-

stances may lose this property, and if the

enantiomorphic compounds possess different de-

grees of pharmacologic action, these changes may

be unacceptable. Other reactions which must be

considered under certain conditions are polymeri-

zatíon and ¡somerization.

Excipients

During preformulation stages, the stability of drug

substance in the presence of pharmaceutical ex-

cipients is extremely valuable to the formulator.

Some excipients can be ruled out based on their

chemical nature and an obvious incompatibility

with the drug of interest. However, this is not true

for the large number of possible drug-excipient

reactions. The use of qualitative techniques for

such studies is frequently satisfactory since the

objective is to detect changes of the drug sub-

stance in the presence of the excipient. The techniques often used are diffu$e reflectance,
spectro-

photometry, thermal techniques, and thin layer

chromatography.

Mixtures containing several levels of drug and ex-

cipient concentrations with known quantities of

moisture are stored under exaggerated conditions

of heat and light for various time periods and then

analyzed both physically and by a suitable qualita-

tive or quantitative analytical technique.

The choice of excipients is another area for pre-

formulation research. The types and levels of im-

purities in certain pharmaceutically “inert” sub-

stances and their physical-chemical characteristics

as they relate to their intended end use is valuable

information to the formulator. However, this area

has been largely neglected to date in the preform-

ulation evaluation. The whole area of excipient

choice and evaluation may be less difficult upon

completion of the Academy of Pharmaceutical Sci-

ences Handbook of Pharmaceutical Excipients.

This project is under the direction of Dr. Jack

Cooper, who conceived the idea of the handbook.

The pharmaceutical industry and pharmaceutical

scientists concerned with dosage form develop-

ment owe a great debt of gratitude to Dr. Cooper

and the many collaborators who have contributed

to this project.

Membrane Permeability

Modern preformulation studies include an early as-

sessment of passage of drug molecules across

biological membranes. As noted earlier, gastroin-

testinal membranes and other membranes of the

body act as lipid barriers to most drugs and permit

the absorption of lipid soluble substances by pas-

sive diffusion. Lipid insoluble substances can cross

the barrier only with considerable difficulty, it at all.

lnterrelationship of the dissociation constant, lipid

solubility, pH at the absorption site, and the ab-

sorption characteristics of various drugs across

membranes are explained by the pH partition the-

ory. The theory has evolved in a series of investi-

gations on laboratory animals and humans, and is

the basis of much of the current understanding of

absorption of drugs.

$MG

Data obtained from basic physical-chemical stud=

es described earlier, specifically, pKa, solubility

(both lipid and aqueous system), and dissolution

rate, is a primary indication of possible absorption

difficulty. Other techniques which add to this pre-

liminary assessment include ¡'n-vitro models in

which the rate of transfer of a drug from an

aqueous system through a “membrane" into a re-

ceptor system have been employed with various

degrees of success.

One such system which has been used exten-

sively with various modifications consists of an

aqueous/organic solvent/aqueous system. This

type of in vitro approach has a great advantage in

its simplicity, and allows for accurate control over

pH, membrane thickness, diffusion layer, mixing,

and other variables. It can be described mathe-

matically in precise terms. However, the interpreta-

tion and correlation of such a system is severely

limited when applied to a biological system. ln par-

ticular, the organic solvents constituting the mem-

brane barrier has only the lipoid property in

common with biological membranes, making ex-

trapolation of rate constants fot transport in the ac-

tual biological system questionable.

A technique which has found favor among many

pharmaceutical scientists in evaluating absorption

characteristics of drug substances is the "everted

intestinal sao." In this method, a piece of intestine

is removed from an intact animal, everted, filled

with a solution of the drug in question, and the

passage of the drug through the membrane sao is

determined. This technique has several advan-=

tages over the simpler organic solvent membrane

system in that both passive and active transport

can be evaluated. Furthermore, the membrane in

this case is a tissue membrane. It has a disadvan-

tage in that this preparation has been removed

from the animal and its normal blood supply.

ln situ models, where an intestinal loop is perfused

with a drug solution, the loss of drug ¡s evaluated

from the profusate. This allows calculation of ab-

sorption rate as well as relative passage through

the biological membrane.

All the techniques described, individually or in total, can give an indication of possible
absorption

problems or suggest that little or no difficulty will

be observed in the passage of the drug product of

interest through the biological membranes. In the

Iatter stages of preformulation testing or early for-

mulation studies in vivo models. animals and

eventually humans must be studied in order to as-

sess the absorption efficiency, pharmacokinetic

parameters, and to establish possible in vitro/in

vivo correlation for dissolution and bioavailability.

This latter information is particularly important in

establishing a dissolution test as a quality control.

This ensures consistent biological performance

from subsequent lots of formulations and assesses

the effects or changes in formulation or processing

on the drug product.

Summary

Development of modern pharmaceuticals requires

that active drug substances be formulated for pa-

tient administration in dosage forms which are

manufacturable on modern-day equipment, stable

through the processing and storage conditions_an-

ticipated, and bioavailable in order to elicit their ex-

pected response. Achievement of these objectives

is facilitated when preformulation evaluation of

the drug substance is part of the developmental

process. A thorough understanding of the physical-

chemical prºperties of the new drug substance is

essential for the efficient develºpment of stable

and efficacious dosage forms. The type and depth

of studies involved are influenced by both the na-

ture of the drug substance and the anticipated

route of administration.

Preformulation studies are accomplished either in

a designated preformulation group or dispersed

throughout various groups within the pharmaceuti-

cal research and development operations. Either

method is acceptable; in any event, the informa-

tion must be obtained sufficiently early in the pro-

gram to be of benefit to the formulation pharma-

cist.

PRE12835

10

Bibliography

1. T. J. Macek: Remington's Pharmaceutical Sciences, Mack Publish-

ing Company. Easton. Pa.. Chap. 75. 1975.

2. E. G. Shami, et al.: The Theory and Practice of Industrial Phar-

macy, Lea and Febiger, Philadelphia, Pa.. Chapter 1, 1976.

3. J. T. Carstensen: Pharmaceuticals of Solids and Solid Dosage

Forms, John Wiley & Sons. New York. NY, 1977.

4. D. 8. Greene: Modern Pharmaceutics. Marcel Dekker, Inc.. New

York. NY. Chap. 6. 1979.

5. D. A. Wadke and H. Jacobson: Pharmaceutical Dosage Forms:

Tablets, Marcel Dekker, Inc.. New York, NY. Chap. 1, 1980.

6. L. J. Ravin: Remington's Pharmaceutical Sciences. Mack Publish-

ing Company, Easton. Pa.. Chap. 75. 1980.

Tablet Processing
This section outlines and describes the primary

methods for making pharmaceutical tablets.

 Wet Granulation

 Direct Compression

 Dry Granulation (Slugging)

Section 2

Tablet Processing

The majority of pharmaceutical dosage forms are

marketed as tablets. To the consumer, tablets of-

fer convenience of administration, handling, identi-

fication, and proper dosage; to the manufacturer,

relatively low cost, and high speed production.

Tablets may be plain, film or sugar coated, bi-

sected, embossed. layered. or sustained release;

they can be made in a variety of sizes, shapes.

and colors. Tablets may be swallowed, chewed,

dissolved in the mouth. or dissolved beneath the

tongue. They may be dissolved in water for local

or tºpical application. Sterile tablets are normally

used for parenteral solutions and for implantation

beneath the skin.

Without excipients most drugs and pharmaceutical

ingredients cannot be directly compressed into

tablets. This is primarily because of the poor flow

and poor cohesive properties of most drugs. Con-

sequently, formulations have to be developed tor

tablet dosage forms which will satisfy the following

basic requirements:

adequate flow of the tableting mix in the ma-

chine hopper and uniform fill into the dies

sufficient cohesive properties to form a firm,

strong tablet under compression

lubricant prºperties which prevent binding of the

tablets and punches in the dies

must not adhere to the punches and dies

uniform drug dose in each tablet

satisfactory release of drug from the tablet after

administration

capability to be processed on high speed pro-

duction equipment

There are three main processes for making com-

pressed tablets:

wet granulation

direct compression (or compaction)

slugging or roll compaction

FMG

Most drugs require the addition of other materials

(excipients) to make a compressed tablet. If the

active component occupies most of the tablet

weight, the excipient must be minimal. At lower

dosage levels, sufticient inert filler is added to

make a tablet of convenient size and weight.

The composition of a powder mix for tableting

should be:

drug

filler

binder

disintegrant

Iubñcant

glidant

antiadherent

excipients
Not all these components may be required to

make a tablet, e.g., some excipients can perform

more than one function.

Choice of filler and other excipients will depend on

the chemical and physical properties of the drug,

behavior of the mixture during processing, and the

properties of the final tablet. It is essential to deter=

mine the chemical and physical compatibility of the

active component with proposed excipients by prec-

formulation studies under stress conditions, e.g.,

elevated temperature and humidity. and exagger-

ated light.

Selection of the best process for tableting will be

determined by the properties of the drug, its dos»

age level, and the economics of the operation. ln

general, in the development of a tablet dosage

form, both wet granulation and direct compression

formulations should be included in the study. How-

ever, wet granulation may be précluded if the drug

is moisture or heat sensitive, if solvent removal is

difficult, or if the economics of the process are un-

satisfactory. Direct compression may not be suit-

able when the drug requires a high dosage and/or

has poor flow and cohesive properties.

Wet Granulation

Wet granulation is the conventional method of con-

verting powders into granules having suitable flow

and cohesive properties for tableting. As the name

implies, a liquid, usually water, is incorporated into

the powders to form a wet mass which can be

dried and processed into a granular form.

A general scheme for the wet granulation process

is outlined below.

Wet granulation

Dry powder blending

Wet massing

Wet granulating

Drying

Dry granulating
Blending

Compression

Flarer do powders have sufticient adhesive or

cohesive properties with water (or other quuids)

alone to form adequately hard and strong granules

when dry. Usually, a binder is required to bond the

powder particles together. Most commonly used

binders are natural or synthetic water soluble

gums; with water sensitive drugs, anhydrous liq-

uids are employed in conjunction with a solvent

soluble binder. (See Binders-Wet Granulation,

Section 3).

Advantages of Wet Granulation

physical characteristics of the drug and ex-

cipients are not usually important

a wide variety of powder materials can be

processed

bulky and dusty powders can be handled

intimate dispersions of low level components

can be controlled

colors can be uniformly dispersed and

duplicated

Disadvantages of Wet Granulation

large number of processing steps-

long processing time-particularly for drying

high labor and manufacturing costs

some material loss during processing

greater possibility of cross contamination

problems associated with heat and water sensi-

tive drugs

material handling problems involving formation

of sticky masses
capital required for extra buildings and equip-

ment

“in-process" costs and working capital

can slow dissolution from granules after tablet

disintegration, particularly upon aging

Excipients

Selection of components for a tablet dosage form

should first be made from preformulation studies.

Chemical and physical stability of the drug in ex-

cipient/drug mixes should be determined under

stress conditions such as elevated temperature

and humidity and exaggerated light.

A list of commonly employed excipients, with their

properties and usage, is given in Section 3.

Dry Blending

Components of the tablet mix should be milled to

a powder form before blending.

It is important to achieve a homogeneous mix in

the dry blending operation in order to have dose

uniformity in the final tablet.

lngredients in small amounts, particularly if they

tend to agglomerate, should be mixed or milled

with a small portion of the filler before blending

with the final mix.

Binders, except starch and gelatin, and those

forming highly viscous solutions, e.g., tragacanth,

can be in<':orporated into the dry mix. Dyes may be

added at this stage.

Disintegrants, lubricants, glidants, and antiadher-

ents are not usually incorporated into the dry

blend.

Wet Massing

Water, solvent, or binder solution is added slowly

and intermittently, with good mixing, to the blended

powder mixture. Adequate mixing time should be

allowed after each addition, particularly at the final

stages to ensure thorough distribution of the liquid.

The end point is the formation of a moist mass

which adheres together when squeezed in the

hand and crumbles between the fingers when the

pressure is released.

With the introduction and use of high speed/high

shear mixers, the end point can be determined

more exactly with the use of devices such as an

amp meter.

Make a note of the liquid volume for future refer-

ence.

Avoid adding too much liquid or overmixing. Both

can result in a sticky, dough-Iike mass which is

difficult or impossible to process. In such cases,

screens can clog in wet granulation, dried granules

can become too hard, compression forces neces-=

sary for tableting can be high, and tablet disinte=

gration may be prolonged.

Frequently during scale-up it has been determined

that less liquid is required to make a satisfactory

mass.

However, insufficient liquid, on the other hand, can

produce soft and powdery granules and probably

soft or fragile tablets. It is important, therefore, that

the granulating fluid be used in an appropriate

quantity for each formulation. Soluble dyes may be

dissolved and incorporated in the liquid for wet

massing.

If the drug is moisture stable, water is generally

used for wet massing in conjunction with a water

soluble binder. Anhydrous solvents, such as ethyl

and ¡sºpropyl alcohols, and methylene chloride,

may be used with moisture sensitive drugs.

Section 3, Binders-Wet Granulation, provides a

listing of commonly used binders and their applica-

tions.

With the exception of starch, gelatin, tragacanth,

and other highly viscous gum solutions, the binder

can be incorporated into the dry mix. Some formu-

lators prefer to incorporate all binders in the solu-

tion.

Starch is typically added to the blended powders

as a 5-10 percent solution in water. This is accom-

plished by adding.the starch powder to boiling

water, mixing, and then heating on a waterbath

until dissolved. Cool before use.

Gelatin is used as a warm 10-20 percent solution

in water. The gelatin is hydrated in cold water first,

then heated on a water bath until dissolved. Pre-

pare fresh material for each batch.

The type and quantity of binder in the formulation

is important. The selection will normally depend on

the physical properties of the powder mix. Pow-

ders with poor hesive qualities may require a

strong binder to make & satisfactory dry granula-

tion and tablet. The tormulator should select suit-

able binders according to their cohesive qualities

and then experiment for optimum granule and tab-

leting properties.

A weak binder or the insufficient use of binder will

produce fragile dry granules with excessive fine

powder (fines) and fragile tablets. A strong binder

or the use of excessive binder will produce hard

granules which are difficult to compress, and often

tablets with poor disintegration prºperties.

Wet Granulation Screening

The moist, powder mix from the wet massing

process is broken up or sub-divided into coarse

aggregates by screening, extruding, chºpping, or

milling. Over-wet material is difficult to process at

this stage.

For small experimental lots, the wet mass may be

forced through a 6 to 8 mesh screen with a hard

wooden block.

Drying
Removal of water or solvent from the wet granula-

tion can be accomplished with many types of

drying equipmentº

The temperature and the rate of drying are ex-

tremely important. They can affect the chemical

stability of drugs and can cause changes in the

powder mix, e.g., sticking, gumming, darkening,

case hardening of the granules, non-uniform

drying, and migration of dyes and drugs to the

granule surface.

The degree of drying should also be considered.

Each powder blend will have an equilibrium mois-

ture content (EMC) at a fixed temperature and hu-

midity. Below this moisture level, the powder will

pick up water; above the EMC, it will lose water.

Theoretically, tablet granulations should be dried

to an EMC of the blend and the processing envi-

ronment. Moisture content can have a pronounced

influence on the tableting behavior of a granula-

tion. Low moisture, e.g., below 1 percent, can

result in some static charge with resultant poor

hopper flow and poor bonding of tablets. These

tablets, as a result, may cap and split. High mois-

ture content can produce weak granules, weak

tablets, and sticking or binding of the punches and

dies. Typically, a moisture content of 1% to 5% is

satisfactory for most formulations.

It is most important to establish and control the

moisture content of dried granulations for optimum

tableting properties.

Dry Granulating

The coarse, dried granulation is reduced to an ap-

propriate particle size by milling or screening. The

following is a guide to the recommended granule

particle size for various diameter tablets:

tablets up to 3/16" diameter, 20 mesh screen

tablets 7/32" to 5/16" diameter, 16 mesh screen

tablets 11/32" to 13/32" diameter, 14 mesh screen

tablets 7/16" diameter and larger, 12 mesh

screen

As high as 20 percent fine powder (fine particles

below 100 mesh) can normally be tolerated in

granulations and can be advantageous in promot-

ing uniform die fill. Fine particles, below 200 cr

325 mesh. can cause flow and tool binding prob-

lems during tableting.

Color distribution problems in dried granulations

can be caused by poorly designed wet granulation

or drying operations (see Drying).

Drug migration during drying (see Drying) can re-

sult in non-unitorm drug distribution in the dried

granulation and therefore in the compressed tab-

lets.

For experimental work, dried granulations may

be sized through the appropriate screen with a

wooden block.

Final Dry Blending

Lubricante. disintegrants, glidants, and antiadher=

ents are normally added to the dried and screened

granulation in the final blend prior to tableting. Lu-

bricants are preferably added through a 100 mesh

screen or bolting cloth and blended for not more

than 5-10 minutes, depending upon the lubricant

used in the formulation.

Mild blending should be used in the final mix. Agi-

tation or excessive shearing action can break up

the granulation.

Avicel PH MCC in

Wet Granulation

Major advantages provided by Avicel© PH-101 and

Avicel PH-102 in the wet granulation process of

tablet making are:

Rapid. even wetting

Wicking action thoroughly distributes the gran-

ulating fluid throughout the powder bed.

Controls wet mass consistency

Large surface area and absorptive capacity

provide wider range of liquid addition without

overwetting.

Less screen blocking

Good wet mass consistency aids in trouble

free screening.

Uniform, rapid drying

Promotes rapid release and evaporation of liq-

uid from the wet granulation.

Controls water soluble drug content uniformity

Regulates active ingredient variation in all par-

ticles of granulation.

Acts as a wet binder

Auxiliary wet binder promotes harder granules

with less fines.

Use of Avicel MCC in post addition step pro-

vides:

excellent binding

high hardness at low pressures

low friability

good disintegration

As a wet massing adjunct, the total quantity of

MCC is added to the initial dry blend. Preferably,

one-half is incorporated into the wet mass and the

remainder into the final blend. If tablet bonding,

capping, or friability is the basic problem, Avicel

is added to the final blend. This post addition of

Avicel is most useful for assurance of trouble-

free tableting when compaction is sensitive to

variations in raw materials or processing.

Direct Compression

Direct compression tableting requires an effective

excipient binder. lt must have good cohesive and

adhesive properties in the dry form and be capa-

ble of bonding other materials to give a hard, com-

pact at low machine pressure. The relative efficacy

of direct compression bi_nders can be measured by

their tablet hardness/compression force profiles.

Microcrystaline cellulose (MCC) provides the high-

est tablet hardness at low machine pressures and

is the most efficient of the direct compression

excipients.

In pharmaceutical tableting, compressibility is a

term sometimes used to describe the binding ca-

pability of direct compression excipients. Avicel

microcrystalline cellulose (MCC) could then be de-

scribed as highly compressible or having high

compressibility.

The relative proficiency of a direct compression

excipient, by itself. to form a strong compact can also be a measure of its ability to bond
other ma-

terials. lts capacity to bind a drug into a strong

tablet under pressure is referred to as dilution po-

tential. Dilution potential can be defined as the

quantity of drug which can be compressed in com-

bination with the excipient to form a tablet having

one percent or less friability. Microcrystalline cellu-

lose has the highest dilution potential of all known

direct compression excipients.

Physical characteristics of the drug and selection

of the appropriate binder must be carefully consid-

ered and controlled. At higher dosage levels, drug

properties of flow and compression will greatly in-

fluence the choice of binder. Even at low dosage

levels, the drug can adversely affect the bonding

of some excipients. Lubricants can also markedly

decrease the compression qualities of many direct

compression binders.-

Once a successful formulation has been devel-

oped, it is important that careful control of the par-

ticle properties be maintained so that uniform

physical and compression qualities of the binder

can be assured.

Advantages of Direct Compression

Tableting

The greatest advantages of direct compression

tableting are time, labor, and capital cost savings.

Direct compression involves only two or three

processing steps compared to many steps for

wet granulation. Materials are "in process" for a

shorter period of time, resulting in less chance for

contamination or cross contamination. and making

it easier to meet good manufacturing practices.

Since no granules are formed, the advantages of

prime particle dissociation become important be-

cause the original active ingredients are com-

pressed without chemical or physical change. The

result is greater chemical and physical stability.

Disadvantages of Direct Compression

While the advantages of direót compression make

this process attractive, there are some limitations

that should be considered. Unlike wet granulation.

the physical limitations of the drug and the physi-

cal properties of raw materials become critical and

must be controlled more precisely. In addition, it is

sometimes necessary to slow the tableting press

to compensate for more difficult formulations. Per-

haps the biggest obstacle faced by direct com-

(Pharm Acta Helv.. 47. 546. 1972)

Ami-FMC trademarx

5W©

pression is the bias of formulators against the

process. ln general, this bias is lesseriing as the

industry becomes more cost conscious, familiar

with the technical process, and aware of the eco-

nomic advantages of direct compression.

Active Components

The physical prºperties of the drug, particularly at

higher dosage levels, are important in direct

compression tableting. Formulation should be di-

rected toward a combination of the most effective

binder and the best physical form of the drug to

give: (a) adequate flow in the hopper, (b) uniform

die fill, and (0) a strong compact without excessive

pressure.

At higher dosage levels, e.g., above 50 percent of

tablet weight, finely powdered drugs, or cohesive

types, are not suitable for direct compression tab-

leting. They often provide problems of flow, non-

uniform die fill. and binding of tooling. A fine gran-

ular or fine crystal form of the drug should gener-

ally be selected. With proper drug qualities and an

effective excipient binder, direct compression tab=

lets can be made containing as high as 80 to 85%

active drug. At higher levels, the drugs must have

inherent flow and binding properties in order to be

compressed directly.

The particle properties of the drug are less critical

at lower dosage levels. However, particle size

should preferably be maintained within the particle

size range of the excipient binder for homogeneity

of powder mix and drug content uniformity of the

tablets.

From a theoretical consideration of randomized

powder mixes, Johnson* has calculated optimum

drug particle sizes for drug content uniformity in

low dosage tablets (Fig. 1). Such particle size dis=

Figure 1

“Limiting particle size" as a function of dose level for

C,, = 1,0%

Drug con [mg'100 mg hblorl

001

O 20 lº en 50 ¡00120140

P……orlwn]

tr¡butrons woum give a value ot 1 percent coeffi-

cient of variation in the mix, corresponding to a

coefficient of variation of drug content in the tablet

of less than 5 percent.

Very low dosage drugs, e.g., 5 mg or less, may be

incorporated into the total mix or portion of the

blend by dissolving in an appropriate volatile sol-

vent, thoroughly mixing with the excipient, and re-

moving the solvent. Ordered blending is another

alternative for making low dosage drugs without

the use of granulating fluids or solvente.

Excipients

Selection of components for a tablet dosage form

should first be made from preformulation studies.

Chemical and physical stability of the drug in drug/

excipient mixes should be determined under stress

conditions such as elevated temperature and hu»

midity and exaggerated light.

A list of commonly used direct compression bind-

ers and other excipients, with properties and

usage, is given in Section 3.

The choice of excipient-binder depends mainly on

the quantity and compression quality of the drug in

the tablet. At higher dosage levels, above 50 per-

cent of the tablet weight, an excipient with a high

dilution potential should be selected. Since the

bonding qualities of some excipients can be ad-

versely affected by even small quantities of drugs,

the binder should always be selected with care.

At lower drug dosage levels, the excipient will gov-

em the homogeneity and the tableting qualities of

the mix. A mix which is too free-flowing can segre»

gate more easily, cause hopper flooding, and un-

even die fill.

The addition of lubricants, particularly magnesium

stearate, is very important. The lubricant should be

added to the final mix through a screen and then

blended to give a uniform distribution. Five min-

utes is generally adequate.

Glidants, such as Cab-O-Sil©, are often used

where the drug flow properties are inadequate.

Dry Blending

Selection of an appropriate mixer is important in

direct compression tableting. It should provide

enough efficiency to adequately produce a homo-

geneous powder blend but should not exert a

Cab-O-Sil-Cabot Corp.

shearing action sufficient to alter the particle size

of the drug or of the excipient-binder.

Homogeneity can be achieved with drug levels of

5-10 percent or more of the powder mix, provided

that adequate blending is accomplished in a suit-

able mixer.

Ordered blending procedures should be used for

lower dosages, or with drugs which agglomerate.

An alternative method is to dissolve the drug in a

volatile solvent, mix with a portion of the excipient

blend, and then remove the sblvent to form a con-

centrate. This concentrate is then added to the en-

tire excipient mix and blended in & suitable mixer.

All components, except lubricants, are normally

added to the initial blend…

Lubricants, in fine or micro-fine form, are screened

(100 mesh) into the mixed powders and blended

for approximately 5 to 10 minutes.

If drugs have flow problems, adhere to the punch

and die, or bind during tableting, it is advanta-

geous to sometimes blend the drug separately

with the lubricant, glidant, and antiadherent and

then add to the excipient-binderº

Over-blending of the powder mix can cause de-

mixing or segregation of the component particles.

The time for optimum mix should be determined

by periodic sampling of the powder blend for con-

tent uniformity. This time can vary for each formu-

lation but generally does not exceed 30 minutes.

Segregation

Particulate solids, once mixed, have a tendency

to segregate due to differences in size, shape,

roughness, and density. This can occur from over

blending and during the subsequent operations of

transfer and tableting. Segregation is particularly

evident in free-flowing materials and can contribute

to nonuniform drug content in tablets.

Segregation can be minimlzed by a narrower parti-

cle size range of both drug and excipient and a re-

duction in free-flow characteristics.

Direct Compression with Avicel Microcrystalline Cellulose

Avicel MCC is one of the most useful excipients

available for direct compression tableting. lts

strong bonding properties and capacity for dry

binding other materials have made MCC a standard by which direct compression excipients
are

ºften cºmpared.

MCC performs many functions in direct compres-

sion:

strong, dry binder

high dilutiºn potential

high tablet hardness at low pressures

low tablet friability

excellent tablet disintegration

flow-aid

inherent lubrication

antiadherent

Types ºf Avicel MCC Available:

Avicel PH-101-the regular grade for tableting; av-

erage particle size 50 microns

Avicel PH-102-a granular form with better flow

and absorptive prºperties; aver-

age particle size 90 micrºns

Avicel PH-103-similar to Avicel PH-101 but with

low moisture cºntent for use with

moisture sensitive drugs; average

particle size 50 micrºns

Avicel PH-105-a fine particle size of MCC which

provides excellent dry binding; av-

erage particle size 20 micrºns

Hºw to Use Avicel MCC

For best results with Avicel MCC in direct cºmpres-

sion, the following approaches are recommended.

Drug Component

lt the drug active level is more than about 65

percent ºf the fºrmula, it should have some in-

herent binding prºperties.

At high dºsage levels, the drug should have

some flow prºperties.

If flow of the powder mix is unsatisfactºry:

use Avicel PH.-102

add 0.1 tº 0.5 percent glidant, e.g., C'ab-O-Sil

use induced feed mechanism on tablet press

improve drug flow qualities, e.g., increase par-

ticle size

dry granulate by slugging active drug with

10-25 percent Avicel PH-102, lubricant, and

add glidant

use rºll cºmpactºr

These suggestions are particularly useful for low

density, microfine, and fluffy drugs such as sulfas

FMIG'

or antibiºtics. Also, this is a good alternative tº the

use ºf alcohol granulatiºn with moisture-sensitive

drugs.

If drug cºntent is less than about 25 to 40 per-

cent of the tablet weight, mixtur'es of Avicel PH-

101 or Avicel PH-102 (10-30 percent) and di-

rectly compressible lactoses or starches may

often be used.

For lºw dºsage tablets (5 mg or less) special

selection of drug particle size ºr drug admixture

may be necessary (see Direct Cºmpression-=

Active Cºmponents).
For successful tableting by direct compression,

control of the physical properties of the compo-

nent powders is essential.

When a tablet has successfully been formulated,

physical properties of the drug, particularly particle

size distribution, must be characterized and con-

trolled. This is critical when the drug level is high,

(greater than 50%).

Lubricants

Although Avicel MCC is self-lubricating, the addition of other materials usually increases the
need for a Iubricant.

Disintegrants

Avicel MCC has excellent disintegration prºperties.

With difficult disintegration problems, the use of

disintegrants such as Ac-Di-Sol© mºdified cellu-

lºse gum or ºther materials may be necessary

(see Tablet lngredients-Disintegrants).

Glidants

lt flºw qualities of the powder mix are inadequate

or erratic, glidants such as the cºlloidal silicas are

useful (see Tablet lngredients-Glidants).

Antiadherents

Avicel MCC is a good antiadherent. In problem

cases, add an antiadherent such as the cºlloidal

silicas (see Tablet Ingredients-Antiadherents).

Blending

The particle size distribution of the powder mix can

be very important in direct compression tableting.

Generally, it can affect both the flow and binding

properties. Therefore, it is important that a mixer, such as the PK© or ribbon blender, be
selected in

order to minimize attrition of the powder particles.

Tableting

Avicel MCC is highly compressible. lt produces

hard, strong tablets at low machine pressures. The

formulator should always aim for the lowest

compression force to give an acceptable tablet

frlabilíty.

Dry Granulation

Slugging and Dry Compaction

Slugging and roll compaction, like direct compres-

sion, are dry methods of processing tablets. Unlike

direct compression, two compaction steps are re-

quired-precompaction and then final tableting.

These processes are typically used when wet

granulation is not feasible or not economical and

the physical properties or level of the drug are

unsuitable for direct compression. High dosage

drugs, microfine or fine powder, which are fluffy or

agglomerate, have poor flow, or poor cohesion

properties, are candidates for the slugging or roll

compaction processes.

The powder blend is compressed under high pres-

sure to give a densified, compacted mass. This is

sized to produce a dry granulation suitable for final

tableting.

Compaction pressure should be sufficient to make

a hard dry granulation. Excessive pressure can re-

sult in a granulation that is too hard. This can

cause tableting problems such as disintegration

and/or dissolution. Usually a large quantity of fines

is produced by dry granulation. These fines must

be recompacted.

Slugging

The powder blend is compressed into large slugs

on a heavy-duty tablet press. Round, flat faced

punches of maximum diameter are used. Since

the powder flow is often poor, a rotary press with

an induced feed device is preferred. A single

punch press with a vibratory hopper can be used.

A lubricant is usually necessary for the slugging process. Addition of a glidant often
improves the Ac-Di-Sol-FMC trademark Pattorson Kelley Trademark flow properties. Other
additives, such as disintegrants, may be added at this stage or incorporated into the final
granulation.
Air entrapment and consequent tablet lamination and Splitting generally are problems
encountered in slugging. Greater clearance between the upper punches and dies allows air
to escape mor'e readily. Tapered dies may be required where air entrapment and tablet
splitting are excessive. A precompression stage on the tablet press is also helpful.

Machine adjustments which can reduce tablet lamination and splitting are: reduce
pressure, reduce speed, reduce depth of fill, compress at the upper portion of the die.

High compression forces are usually required for slugging. Some materials are not
sufficiently cohesive at maximum machine pressures to form slugs or cannot be densified
sufficiently to form hard granules. Addition of Avicel MCC (5-15 percent) to the powder
blend is very effective and helps to produce a hard granulation with minimum fines.

Avicel MCC also is a good binder for the final tableting.

Dry Compaction

For large scale production, the slugging method can be an expensive and slow operation.
Roll compaction is an efficient, continuous process.

The process blend is fed from a hopper between two variable high pressure rollers to form
thin compacted sheets. This process is capable of high speed production, but adequate flow
of the powder blend is important. It may be necessary to use a glidant, but a lubricant is not
generally required.

Addition of a binder, (Avicel MCC from 5-15 percent), may be necessary where cohesion is
inadequate and too many fines occur during granulation.

Final Compression

The compacted material is sized to a suitable particle size (see Wet Granulation-Dry
Granulating) using a mill or an oscillating granulator. Additives, such as lubricants and
disintegrants , are blended carefully to avoid attrition of the granulation. The final blend is
then compressed into tablets and excess fines from the dry granulation process are
recompacted .